The characteristic neuropathological deposits identified in Alzheimer's disease (AD) are the extracellular amyloid beta (A) plaques and intracellular tau tangles. Neurofibrillary degeneration in the absence of - amyloid, is also seen in several tauopathies such as Guam parkinsonism dementia complex, dementia pugilistica, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy. It is well established that hyperphosphorylation of tau is responsible for the neurofibrillary lesions found in these conditions, while A, a cleavage product of the amyloid precursor protein (APP), is a main constituent of the plaques. The interrelationship between hyperphosphorylated tau and A has been well studied, however, new functions for tau in signaling and cytoskeletal organization have emerged that challenge previously held paradigms (Morris et al., 2011). Studies have also shown that reduction in wild-type tau prevents A-dependent behavioral and cognitive deficits (Roberson et al., 2007), suggesting that therapeutic interventions that alter the levels of tau may be beneficial. The transcription factor specificity protein 1 (Sp1) is essential for the regulationof the tau gene and its cyclin dependent kinase 5 (CDK5). Studies from our lab have provided convincing evidence that either silencing of the Sp1 gene using small interfering RNA (Basha et al., 2005) or treatment of animals with tolfenamic acid lowers the expression of AD-related Sp1 target genes (Adwan et al., 2011). Preliminary data from our lab have also demonstrated that tolfenamic acid can reduce tau protein and mRNA levels in animal models. Tolfenamic acid has been approved for human use in migraine headaches in Europe. Therefore, it affords potential as a repurposed drug for rapid development with limited concerns about its toxicity in humans. In this proposal, we intend to examine if tolfenamic acid can interfere with the regulation of the tau gene and alter the levels of its product and examine the impact of such alterations on the phosphorylation of tau and its immunohistopathological distribution in htau transgenic mice.